The present invention-relates to the use of biodegradable, pH/thermosensitive hydrogels, consisting of a A-B-A tri block copolymer of poly(d,l- or l-lactic acid) (PLA) or poly(lactide-co-glycolide) (PLGA) (block A) and polyethylene glycol (PEG) (block B), with ionizable functional groups on one or both ends of the polymer chains, for the sustained delivery of biologically active agents.
Due to recent advances in genetic and cell engineering technologies, proteins known to exhibit various pharmacological actions in vivo are capable of production in large amounts for pharmaceutical applications. Such proteins include erythropoietin (EPO), novel erythrbpoiesis stimulating protein (NESP), granulocyte colony-stimulating factor (G-CSF), interferons, (alpha, beta, gamma, consensus), tumor necrosis factor binding protein TNFbp), interleukin-1 receptor antagonist (IL-1ra), brain-derived neurotrophic factor (BDNF), kerantinocyte growth factor (KGF), stem cell factor (SCF), megakaryocyte growth differentiation factor (MGDF), osteoprotegerin (OPG), glial cell line derived neurotrophic factor (GDNF) and obesity protein (OB protein). OB protein may also be referred to herein as leptin.
Because proteins such as leptin generally have short in vivo half-lives and negligible oral bioavailability, they are typically administered by frequent injection, thus posing a significant physical burden on the patient (e.g., injection site reactions are particularly problematic with many leptin formulations) and associated administrative costs. As such, there is currently a great deal of interest in developing and evaluating sustained-release formulations. Effective sustained-release formulations can provide a means of controlling blood levels of the active ingredient, and also provide greater efficacy, safety, patient convenience and patient compliance. Unfortunately, the instability of most proteins (e.g. denaturation and loss of bioactivity upon exposure to heat, organic solvents, etc.) has greatly limited the development and evaluation of sustained-release formulations.
Biodegradable polymer matrices have thus been evaluated as sustained-release delivery systems. Attempts to develop sustained-release formulations have included the use of a variety of biodegradable and non-biodegradable polymer (e.g. poly(lactide-co-glycolide)) microparticles containing the active ingredient (see e.g., Wise.et al., Contraception, 8:227-234 (1973); and Hutchinson et al., Biochem. Soc. Trans., 13:520-523 (1985)), and a variety of techniques are known by which active agents, e.g. proteins, can be incorporated into polymeric microspheres (see e.g., U.S. Pat. No. 4,675,189 and references cited therein).
Utilization of the inherent biodegradability of these materials to control the release of the active agent and provide a more consistent sustained level of medication provides improvements in the sustained release of active agents. Unfortunately, some of the sustained release devices utilizing microparticles still suffer from such things as: active agent aggregation formation; high initial bursts of active agent with minimal release thereafter; and incomplete release of active agent.
Other drug-loaded polymeric devices have also been investigated for long term, therapeutic treatment of various diseases, again with much attention being directed to polymers derived from alpha hydroxycarboxylic acids, esptcially lactic acid in both its racemic and optically active form, and glycolic acid, and copolymers thereof. These polymers are commercially available and have been utilized in FDA-approved systems, e.g., the Lupron Depot(trademark), which consists of injectable microcapsules which release leuprolide acetate for about 30 days for the treatment of prostate cancer.
Various problems identified with the use of such polymers include: inability of certain macromolecules to diffuse out through the matrix; deterioration and decomposition of the drug (e.g., denaturation caused by the use of organic solvents); irritation to the organism (e.g. side effects due to use of organic solvents); low biodegradability (such as that which occurs with polycondensation of a polymer with a multifunctional alcohol or multifunctional carboxylic acid, i.e., ointments); and slow rates of degradation.
The use of polymers which exhibit reverse thermal gelation have also been reported. For example, Okada et al., Japanese Patent Application 2-78629 (1990) describe biodegradable block copolymers synthesized by transesterification of poly(lactic acid) (PLA) or poly(lactic acid)/glycolic acid (PLA/GA) and poly(ethylene glycol) (PEG). PEGs with molecular weights ranging from 200 to 2000, and PLA/GA with molecular weights ranging from 400 to 5000 were utilized. The resultant product was miscible with water and formed a hydrogel. The Okada et al. reference fails to provide any demonstration of sustained delivery of drugs using the hydrogels.
Cha et al., U.S. Pat. No. 5,702,717 describe systems for parenteral delivery of a drug comprising an injectable biodegradable block copolymeric drug delivery liquid having reverse thermal gelation properties, i.e., ability to form semi-solid gel, emulsions or suspension at certain temperatures. Specifically, these thermosensitive gels exist as a mobile viscous liquidat low temperatures, but form a rigid semisolid gel at higher temperatures. Thus, it is possible to use these polymers to design a formulation which is liquid at room temperature or at lower temperatures, but gels once injected, thus producing a depot of drug at the injection site. The systems described by Cha et al. utilize a hydrophobic A polymer block comprising a member selected from the group consisting of poly(xcex1-hydroxy acids) and poly(ethylene carbonates) and a hydrophilic B polymer block comprising a PEG. The Cha et al. system requires that less than 50% by weight hydrophobic A polymer block be utilized and greater than 50% by weight hydrophilic B polymer block be utilized. Interestingly, however, it appears that several of the disclosed hydrogels might not be commercially useful in that the lower critical solution temperature (LCST) for many of the gels is greater than 37xc2x0 C. Although Cha et al. propose use of their hydrogels for controlled release of drugs, no such demonstration is provided.
Churchill et al., U.S. Pat. No. 4,526,938, describe a continuous release composition comprising a biodegradable (PLGA/PEG) block copolymer admixed with a drug which is continuously released from the block copolymer. The example described in Churchill et al. uses 50%/50% weight percentage copolymer. Churchill et al. do not discuss whether the compositions exhibit reverse thermal gelation properties, nor teach aqueous solutions of drug-containing block copolymers that are soluble at the time of injection and that undergo gelation as they reach body temperature. Rather, Churchill et al. teach administration of a block copolymer in solid form.
Martini et al., J. Chem. Soc., 90(13):1961-1966 (1994) describe low molecular weight ABA type tri block copolymers which utilize hydrophobic poly(xcex5-caprolactone) (PCL), and PEG Unfortunately, in vitro degradation rates for these copolymers was very slow, thus calling into question their ability as sustained-release systems.
Stratton et al., PCT/US97/3479 (WO 98/02142) Jan. 22, 1998, describe pharmaceutical compositions comprising a polymeric matrix having thermal gelation properties, for the delivery of proteins. The class of block copolymers described are generically referred to as polyoxyethylene-polyoxypropylene condensates (also known as Pluronics). Unfortunately, only high molecular weight Pluronics at higher concentrations (25-40 wt. %) exhibit thermoreversible gelation, and the very nature of gelation caused by formation of densely packed liquid crystalline phases in concentrated Pluronic solutions limits the applicability of Pluronics in drug delivery.
Kim et al., J. Appl. Polym. Sci., 45:1711 (1992) describe various pH-sensitive hydrogels and the use of such hydrogels to fabricate a glucose-sensitive insulin release device.
Chen and Hoffman, Nature, 373:49-52 (1995) described a new generation of xe2x80x98intelligentxe2x80x99 copolymers of thermogelling surfactants and pH-responsive bioadhesive polymers containing ionizable carboxylic groups, that obtain pH and temperature sensitivity. The polymers are prepared by grafting a temperature-sensitive polymer (PNIPAAm) onto a pH-sensitive polymer (PAAc) backbone, and have been shown to possess bioadhesive properties due to the backbone polymer. It is necessary to obtain a graft (or block) copolymer because it was found that random copolymers of the temperature- and pH-sensitive monomers lose their temperature-sensitivity at body temperatures when the levels of the pH-sensitive component are high enough to obtain a sufficiently bioadhesive material. Drawbacks to the copolymers described by Chen and Hoffman are the potentially poor biocompatibility and non-biodegradability of PNIPAAm polymers, and the fact that drugs contained within some NIPAAm-containing hydrogels are known to be effectively squeezed out of the hydrogel as the hydrogel collapses, leading to a burst of drug each time the gel collapses, which is not ideal for sustained drug delivery.
Lee et al., J. Appl. Polym. Sci., 62:301-311 (1996) report on the preparation and swelling properties of pH- and temperature-dependent poly(vinyl alcohol) (PVA)/poly(acrylic acid) (PAAc) interpenetrating polymer networks (IPN) hydrogels by a unique freezing-thawing method. It was reported that the hydrogels showed both positive and negative swelling behaviors depending on PAAc content. It is postulated that the hydrogels could be strong candidates as drug delivery materials, but there is no demonstration of such use.
It is the object of the present invention to provide biodegradable, pH/termosensitive hydrogels for the sustained delivery of drugs. The hydrogels of the present invention utilize copolymer compositions containing ionizable functional groups which provide for instant gelation with trapping of all the biologically active agent within the gel, i.e., no burst, and, importantly, which upon injection, possess improved rates of degradation, de-gelation and clearance of the depot from the injection site, making this class of hydrogels more commercially practical than those previously described.
In one embodiment, the present invention provides pharmaceutical compositions comprising an effective amount of a biologically active agent incorporated into a polymeric matrix, said polymeric matrix comprising a di block or tri block copolymer which is thermosensitive, exhibits pH-responsive gelation/de-gelation, and is capable of providing for the sustained-release of the biologically active agent.
In another embodiment, the present invention provides a method for the parenteral administration of a biologically active agent in a biodegradable polymeric matrix to a warm blooded animal, wherein a gel depot is formed within the body of said animal and the biologically active agent is released from the depot at a controlled rate concomitant with biodegradation of the polymeric matrix